Impaired peroxisomal function in the central nervous system with inflammatory disease of experimental autoimmune encephalomyelitis animals and protection by lovastatin treatment

• Published in: Brain research Vol. 1022; no. 1; pp. 1 - 11
• Main Authors: Singh, Inderjit, Paintlia, Ajaib S., Khan, Mushfiquddin, Stanislaus, Romesh, Paintlia, Manjeet K., Haq, Ehtishamul, Singh, Avtar K., Contreras, Miguel A.
• Format: Journal Article
• Language: English
• Published: London Elsevier B.V 01-10-2004; Amsterdam Elsevier; New York, NY
• Subjects: Acyl-CoA Oxidase - genetics; Acyl-CoA Oxidase - metabolism; Acyltransferases - metabolism; Adenosine Triphosphatases - metabolism; Animals; Anticholesteremic Agents - therapeutic use; ATP-Binding Cassette Transporters - metabolism; ATPases Associated with Diverse Cellular Activities; Biological and medical sciences; Catalase - metabolism; Central Nervous System - drug effects; Central Nervous System - metabolism; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental - chemically induced; Encephalomyelitis, Autoimmune, Experimental - complications; Encephalomyelitis, Autoimmune, Experimental - prevention & control; Experimental autoimmune encephalomyelitis; Fatty Acids - metabolism; Female; Freund's Adjuvant; Immunohistochemistry - methods; Inflammation - etiology; Inflammation - prevention & control; Lovastatin - therapeutic use; Medical sciences; Membrane Proteins - metabolism; Microarray Analysis - methods; Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis; Neuroinflammation; Neurology; Peroxisomal Disorders - etiology; Peroxisomal Disorders - prevention & control; Peroxisome; Peroxisomes - drug effects; Peroxisomes - physiology; Rats; Rats, Inbred Lew; Reverse Transcriptase Polymerase Chain Reaction - methods; RNA, Messenger - biosynthesis; Statin; Peroxisome; Experimental autoimmune encephalomyelitis; Disorders of the nervous system; Neuroinflammation; Statin; Autoimmunity; Nervous system diseases; Rat; Rodentia; Central nervous system; Lovastatin; Statin derivative; Vertebrata; Experimental disease; Mammalia; Animal
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2004.06.059

Peroxisomes are ubiquitous subcellular organelles and abnormality in their biogenesis and specific gene defects leads to fatal demyelinating disorders. We report that neuroinflammatory disease in brain of experimental autoimmune encephalomyelitis (EAE) rats decreased the peroxisomal functions. Degradation of very long chain fatty acids decreased by 47% and resulted in its accumulation (C26:0, 40%). Decreased activity (66% of control) of dihydroxyacetonephosphate acyltransferase (DHAP-AT), first enzyme in plasmalogens biosynthesis, resulted in decreased levels of plasmalogens (16–30%). Catalase activity, a peroxisomal enzyme, was also reduced (37%). Gene microarray analysis of EAE spinal cord showed significant decrease in transcripts encoding peroxisomal proteins including catalase (folds 3.2;
p<0.001) and DHAP-AT (folds 2.6;
p<0.001). These changes were confirmed by quantitative reverse transcription polymerase chain reaction (RT-PCR) analysis, suggesting that decrease of peroxisomal functions in the central nervous system will have negative consequences for myelin integrity and repair because these lipids are major constituents of myelin. However, lovastatin (a cholesterol lowering and anti-inflammatory drug) administered during EAE induction provided protection against loss/down-regulation of peroxisomal functions. Attenuation of induction of neuroinflammatory mediators by statins in cultured brain cells [J. Clin. Invest. 100 (1997) 2671–2679], and in central nervous system of EAE animals and thus the EAE disease [J. Neurosci. Res. 66 (2001) 155–162] and the studies described here indicate that inflammatory mediators have a marked negative effect on peroxisomal functions and thus on myelin assembly and that these effects can be prevented by treatment with statins. These observations are of importance because statins are presently being tested as therapeutic agents against a number of neuroinflammatory demyelinating diseases.